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The marine Penicillium sp. GGF16-1-2 metabolite dicitrinone G inhibits pancreatic angiogenesis by regulating the activation of NLRP3 inflammasome

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Abstract

Citrinin derivatives have been found to have various pharmacological activities, such as anti-inflammatory, anti-tumor, and antioxidant effects. Dicitrinone G (DG) was a new citrinin dimer isolated from marine-derived fungus Penicillium sp. GGF 16-1-2 which has potential activity. Here, we aim to investigate whether DG has anti-pancreatic cancer activity. In xenograft tumor model, 2 × 106 BXPC-3 cells were injected into the hind flank of NU/NU nude mice by subcutaneously for 2 weeks followed by treating with DG (0.25, 0.5, 1 mg/kg) and 5-FU (30 mg/kg) for 4 weeks. Tumor volume and weight were measured, and the expression of CD31, IL-18, NLRP3, and Caspase-1 in tumor tissue were detected. In vitro, HUVECs were treated with conditioned medium (CM) derived from BXPC-3 cells, the effects of DG on angiogenesis were detected by tube formation and western blot analysis. In vivo studies showed that the tumor growth and angiogenesis were greatly suppressed. The tumor weight inhibition rates of DG and 5-FU groups were about 42.36%, 38.94%, 43.80%, and 31.88%. Furthermore, the expression of CD31 and Caspase-1 were decreased. In vitro, CM derived from BXPC-3 cells which treated with DG could inhibit the tube formation and expression of pro-angiogenic NICD in HUVECs. Our study suggests that DG could suppress angiogenesis via the NLRP3/IL-18 pathway and may have the potential to inhibit tumor development.

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Acknowledgements

We thank all the participants for their interest on this study.

Funding

This work was financially supported the Special Project for Marine Economic Department of Natural Resources of Guangdong Province (GDNRC[2021]48, GDNRC[2023]37 and GDNRC [2020]039); the National Natural Science Foundation of China (No. 82274130, No. 82273845 and No. 81741160); National Key Research and Development Program of China (2017YFC1700400 and 2017YFC1700404); Guangdong Natural Science Funds for Distinguished Young Scholars (20181B030306027); Major Program of Science and Technology Program of Guangzhou (202103000044); Special Program for Key Fields of Colleges and Universities of Guangdong (2021ZDZX2041) and Wuhan Health Research Fund (WZ20Y03); Hubei Provincial Natural Science Foundation of China (2021CFB424).

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Author notes

  1. Zhimian Shi, Minyi Zhang, and Hao Fan contributed equally to this work.

Authors and Affiliations

  1. School of Pharmaceutical Sciences, Guangzhou Higher Education Mega Center, Guangzhou University of Chinese Medicine, 232, Waihuan East Road, Panyu, Guangzhou, 510000, China

    Zhimian Shi, Minyi Zhang, Hao Fan, Yijun Chen, Fengguo Zhou, Jingya Liu, Jiaqi Jin, Yong Luo, Qiuhe Chen, Wei Wang, Cuixian Zhang & Yang Chen

  2. Guangdong Key Laboratory of TCM Pathogenesis and Prescriptions Realted to Heart and Spleen, Guangzhou Higher Education Mega Center, 232, Waihuan East Road, Panyu, Guangzhou, 510000, China

    Zhimian Shi, Minyi Zhang, Yijun Chen, Yong Luo, Qiuhe Chen, Wei Wang & Yang Chen

  3. Department of Pharmacy, People’s Hospital of Dongxihu District, Wuhan, 430040, Hubei, China

    Su Dong

  4. Department of Cardiovascular Ultrasound, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China

    Bin Wang

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Contributions

ZS, MZ, HF, YC, SD, FZ, JL, JJ, YL, and QC performed the experiments and collected the data; ZS and YC analyzed the data; WW, CZ, and YC discussed the results and commented on the manuscript; YC designed the study and wrote the manuscript; BW corrected the grammar mistakes in the revised manuscript, ZS, MZ, HF contributed equally to this study. All authors have read and agreed to the version of the manuscript.

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Correspondence to Wei Wang, Cuixian Zhang or Yang Chen.

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Shi, Z., Zhang, M., Fan, H. et al. The marine Penicillium sp. GGF16-1-2 metabolite dicitrinone G inhibits pancreatic angiogenesis by regulating the activation of NLRP3 inflammasome. J Nat Med 78, 78–90 (2024). https://doi.org/10.1007/s11418-023-01749-z

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